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WASHINGTON, DC—Preclinical research suggests a second-generation BTK inhibitor may overcome the acquired resistance observed with its predecessor in patients with chronic lymphocytic leukemia (CLL).
Investigators found the non-covalent BTK inhibitor SNS-062 was unaffected by the BTK C481S mutation, which confers resistance to the first-generation BTK inhibitor ibrutinib.
“[A] subset of patients acquire resistance to ibrutinib, the current standard-of-care BTK inhibitor,” said Amy Johnson, PhD, of The Ohio State University in Columbus.
“A key resistance mechanism to covalent BTK inhibitors is a point mutation in the BTK active site, converting cysteine 481 to serine, or C481S.”
“In this study, we demonstrate that SNS-062, which binds non-covalently to BTK, is a potent inhibitor of BTK unaffected by the presence of the C481S mutation. These findings support clinical investigation of SNS-062 to address acquired resistance to covalent BTK inhibitors in patients.”
Dr Johnson and her colleagues presented these findings at the AACR Annual Meeting 2017 (abstract 1207).
SNS-062 is being developed by Sunesis Pharmaceuticals, Inc., and company investigators were involved in this research. But the study was sponsored by The Ohio State University.
For this study, Dr Johnson and her colleagues tested SNS-062 in primary CLL cells and X-linked agammaglobulinemia human cell lines.
The investigators found that SNS-062 inhibited BTK, decreased the expression of B-cell activation markers, and reduced CLL cell viability in a dose-dependent manner. And these effects were comparable to those observed with ibrutinib.
SNS-062 and ibrutinib demonstrated comparable activity against wild-type BTK. However, ibrutinib and another BTK inhibitor, acalabrutinib, were hindered by the BTK C481S mutation, while SNS-062 was not.
The investigators said SNS-062 was 6 times more potent than ibrutinib against C481S BTK and more than 640 times more potent than acalabrutinib.
The team also noted that SNS-062 exhibited high specificity, affecting a limited number of kinases outside the TEC kinase family.
Finally, the investigators found that SNS-062 diminished stromal cell protection in CLL cells, suggesting the drug can hinder protection from the tumor microenvironment. 
WASHINGTON, DC—Preclinical research suggests a second-generation BTK inhibitor may overcome the acquired resistance observed with its predecessor in patients with chronic lymphocytic leukemia (CLL).
Investigators found the non-covalent BTK inhibitor SNS-062 was unaffected by the BTK C481S mutation, which confers resistance to the first-generation BTK inhibitor ibrutinib.
“[A] subset of patients acquire resistance to ibrutinib, the current standard-of-care BTK inhibitor,” said Amy Johnson, PhD, of The Ohio State University in Columbus.
“A key resistance mechanism to covalent BTK inhibitors is a point mutation in the BTK active site, converting cysteine 481 to serine, or C481S.”
“In this study, we demonstrate that SNS-062, which binds non-covalently to BTK, is a potent inhibitor of BTK unaffected by the presence of the C481S mutation. These findings support clinical investigation of SNS-062 to address acquired resistance to covalent BTK inhibitors in patients.”
Dr Johnson and her colleagues presented these findings at the AACR Annual Meeting 2017 (abstract 1207).
SNS-062 is being developed by Sunesis Pharmaceuticals, Inc., and company investigators were involved in this research. But the study was sponsored by The Ohio State University.
For this study, Dr Johnson and her colleagues tested SNS-062 in primary CLL cells and X-linked agammaglobulinemia human cell lines.
The investigators found that SNS-062 inhibited BTK, decreased the expression of B-cell activation markers, and reduced CLL cell viability in a dose-dependent manner. And these effects were comparable to those observed with ibrutinib.
SNS-062 and ibrutinib demonstrated comparable activity against wild-type BTK. However, ibrutinib and another BTK inhibitor, acalabrutinib, were hindered by the BTK C481S mutation, while SNS-062 was not.
The investigators said SNS-062 was 6 times more potent than ibrutinib against C481S BTK and more than 640 times more potent than acalabrutinib.
The team also noted that SNS-062 exhibited high specificity, affecting a limited number of kinases outside the TEC kinase family.
Finally, the investigators found that SNS-062 diminished stromal cell protection in CLL cells, suggesting the drug can hinder protection from the tumor microenvironment.
WASHINGTON, DC—Preclinical research suggests a second-generation BTK inhibitor may overcome the acquired resistance observed with its predecessor in patients with chronic lymphocytic leukemia (CLL).
Investigators found the non-covalent BTK inhibitor SNS-062 was unaffected by the BTK C481S mutation, which confers resistance to the first-generation BTK inhibitor ibrutinib.
“[A] subset of patients acquire resistance to ibrutinib, the current standard-of-care BTK inhibitor,” said Amy Johnson, PhD, of The Ohio State University in Columbus.
“A key resistance mechanism to covalent BTK inhibitors is a point mutation in the BTK active site, converting cysteine 481 to serine, or C481S.”
“In this study, we demonstrate that SNS-062, which binds non-covalently to BTK, is a potent inhibitor of BTK unaffected by the presence of the C481S mutation. These findings support clinical investigation of SNS-062 to address acquired resistance to covalent BTK inhibitors in patients.”
Dr Johnson and her colleagues presented these findings at the AACR Annual Meeting 2017 (abstract 1207).
SNS-062 is being developed by Sunesis Pharmaceuticals, Inc., and company investigators were involved in this research. But the study was sponsored by The Ohio State University.
For this study, Dr Johnson and her colleagues tested SNS-062 in primary CLL cells and X-linked agammaglobulinemia human cell lines.
The investigators found that SNS-062 inhibited BTK, decreased the expression of B-cell activation markers, and reduced CLL cell viability in a dose-dependent manner. And these effects were comparable to those observed with ibrutinib.
SNS-062 and ibrutinib demonstrated comparable activity against wild-type BTK. However, ibrutinib and another BTK inhibitor, acalabrutinib, were hindered by the BTK C481S mutation, while SNS-062 was not.
The investigators said SNS-062 was 6 times more potent than ibrutinib against C481S BTK and more than 640 times more potent than acalabrutinib.
The team also noted that SNS-062 exhibited high specificity, affecting a limited number of kinases outside the TEC kinase family.
Finally, the investigators found that SNS-062 diminished stromal cell protection in CLL cells, suggesting the drug can hinder protection from the tumor microenvironment.